Taxane derivatives

ABSTRACT

Taxane derivatives modified at 13-position of the taxane derivative skeleton (taxol numbering) of formula (I), wherein R, R a , R b , R c , R 1 , R 2 , R 3  are appropriate organic residues can be antitumor agents.

This application is a 371 of PCT/EP 95/04302 dated Nov. 2, 1995.

The present invention is directed to new taxane derivatives endowed withantitumour activity, to a process for their preparation and topharmaceutical compositions containing them.

The taxane family of direrpenes includes Paclitaxel (also named taxol inseveral publications), isolated and characterized from an extract ofbark of Taxus brevifolia L., and Cephalomannine (see J. Chem. Soc. Chem.Comm. 102, 1979); other taxane analogues are also known and wereprepared by semisynthesis starting from 10-deacetyl baccatin III,extracted from the needles of Taxus baccata L. (see Wani et al., J. Am.Chem. Soc. 93, 2325, 1971; Lovelle et al., Proc. Am. Assoc. Cancer Res.31, 417, 1990). Particularly, paclitaxel is a very potent anticancerdrug and is already applied with success to the treatment ofplatinum-resistant ovarian cancer. Nevertheless there is a continuousneed for more potent compounds having the broadest possible spectrum ofactivity on different cancer types.

The present invention provides taxane derivatives modified at the13-position of the taxane skeleton (taxol numbering). More especially,the invention provides taxane derivatives of the formula I: ##STR1##wherein: R represents a hydrogen atom or a hydroxy group, or takentogether with R₃, a bond;

(i) R_(a) and R_(c) are hydrogens and R_(b) is hydroxy, or

(ii) R_(a) and R_(b) taken together form a bond and R_(c) is hydrogen,or

(iii) R_(a) is hydrogen atom and R_(b) and R_(c) taken together form abond, or R_(b) is azido or amino group and R_(c) is hydrogen atom;

R₁ represents a hydrogen atom, a hydroxy group or a residue of formula--OCOR', --OR', --OSO₂ R', --OCONR'R", --OCONHR' or --OCOOR' wherein R'and R" are each independently C₁ -C₆ alkyl, preferably methyl, phenyl-C₂-C₆ alkenyl or phenyl-C₂ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₂ -C₆ alkynyl ora phenyl group, optionally substituted with one, two or threesubstituents which may be the same or different and which are selectedfrom a halogen atom and C₁ -C₆ alkyl, C₁ -C₆ alkoxy and --CF₃ groups;and either

(i) R₂ and R₃ together represent a group of the formula A--N═, as pure Eor pure Z isomers or as a mixture of both E and Z isomers, wherein Arepresents:

a hydrogen atom or a hydroxy, methoxy, acetoxy, amino, methylamino ordimethylamino group, or

a group of the formula Y--NH-- wherein Y represents either

(a) residue of an amino acid, preferably glycine, phenylglycine, serine,3-phenylserine, β-alanine and the like, optionally protected at theamino group as a N-benzoyl derivative or as a carbamate, or

(b) a chain of the formula II: ##STR2## wherein: R₄ is a C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl group or a phenyl or heteroaryl group,optionally substituted with one, two or three substituents which may bethe same or different and which are selected from a halogen atom and C₁-C₆ alkyl, C₁ -C₆ alkoxy, or --CF₃ groups; and

R₅ is --COOR'" or --COR'" or CONHR'" wherein R'" is C₁ -C₆ alkyl,preferably tert-butyl or n-pentyl, C₂ -C₆ alkenyl, preferably1-methyl-1-propenyl, C₃ -C₆ cycloalkyl, C₂ -C₆ alkynyl or a phenylgroup, optionally substituted with one, two or three substituents whichmay be the same or different and which are selected from a halogen atomand C₁ -C₆ alkyl, C₁ -C₆ alkoxy and --CF₃ groups; or

a group of the formula Y or Y--O-- wherein Y is as defined above;

a group of the formula COR' wherein R' is as defined above; or

(ii) R₂ represents a group of the formula B--NH-- wherein B represents

a) hydrogen atom,

b) hydroxy group,

c) amino group,

d) a group of the formula Y--(NH)_(n) -- wherein Y is as defined aboveand n is 0 or 1, or

e) a group of the formula Y--O-- wherein Y is as defined above;

f) a group of the formula COR' wherein R' is as defined above; and R₃represents hydrogen, or, taken with R, a bond; and pharmaceuticallyacceptable salts thereof.

The R₂ substituent may be in the R or S configuration. Alternatively theR₂ substituent may be in both the R and S configurations i.e. a mixtureof stereoisomers is present.

A C₁ -C₆ alkyl group is a straight or branched alkyl group, preferably aC₁ -C₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl or n-pentyl. A C₂ -C₆ alkenyl group is astraight or branched alkenyl group, preferably a C₂ -C₅ alkenyl groupsuch as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl,butenyl or pentenyl. A C₃ -C₆ cycloalkyl group is a saturatedcarbocyclic group of 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

A halogen is preferably fluorine, chlorine, bromine or iodine.

The heteroaryl group is preferably a 3- to 6-membered, saturated orunsaturated heterocyclyl ring which contains at least one, for example1, 2 or 3, heteroatoms selected from O, S and N and which is optionallyfused to a second 5- or 6-membered, saturated or unsaturatedheterocyclyl group containing 1 or more, for example, 1, 2, or 3hetereoanoms or to a cycloalkyl group or to an aryl group. The 3- to6-membered heterocycyl ring may be a 3-, 4-, 5- or 6- membered suchring. A cycloalkyl group is generally a said C₃ -C₆ cycloalkyl group. Anaryl group is generally phenyl or naphthyl.

Examples of heterocyclyl groups are pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, thienyl, furyl, aziridinyl, oxiranyl, azetidinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, benzothienyl,benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, chromenyl,indolyl, indolizinyl, isoindolyl, cinnolinyl, indazolyl and purinyl.

A C₂ -C₆ alkenediyl chain can be a straight or branched alkenediylpreferably a C₂ -C₄ alkenediyl chain such as --CH═CH--, --CH═CH--CH₂ --or --CH(CH₃)--CH═CH--. The C₂ -C₆ alkynyl group is a straight orbranched alkynyl group preferably a C₂ -C₄ alkynyl chain such asethynyl, propargyl, 1-propynyl, 1-butynyl or 2-butynyl. A C₁ -C₆ alkoxygroup can be a straight chain or branched alkoxy group, preferably a C₁-C₄ alkoxy group such as methoxy, ethoxy, n-propoxy, n-butoxy ortert-butoxy.

Preferred compounds of the invention are taxane derivatives of formulaI, wherein:

R_(a) and R_(c) are hydrogen atoms and R_(b) is hydroxy, R₁ represents ahydrogen atom, a hydroxy group or a residue of formula --OCOR', --OR',--OSO₂ R', --OCONR'R", --OCONHR' or --OCOOR' wherein R' and R" are eachindependently C₁ -C₄ alkyl, C₂ -C₅ alkenyl, C₃ -C₆ cycloalkyl, C₂ -C₅alkynyl or a phenyl group, optionally substituted with one, two or threesubstituents which may be the same or different and which are selectedfrom a halogen atom and C₁ -C₄ alkyl, C₁ -C₄ alkoxy and --CF₃ groups;and either:

(i) R₂ and R₃ together represent a group of the formula A--N═, as pure Eor pure Z isomers or as a mixture of both E and Z isomers, wherein Arepresents:

a hydrogen atom, a hydroxy, methoxy, acetoxy, amino, methylamino ordimethylamino groups, or

a group of the formula Y--NH-- wherein Y represents either

(a) residue of an amino acid optionally protected at the amino group asa N-benzoyl derivative or as a carbamate, or

(b) a chain of the formula II: ##STR3## wherein: R₄ is a C₁ -C₄ alkyl,C₂ -C₅ alkenyl, C₃ -C₆ cycloalkyl group or a phenyl or heteroaryl group,optionally substituted with one, two or three substituents which may bethe same or different and which are selected from a halogen atom and C₁-C₄ alkyl, C₁ -C₄ alkoxy and --CF₃ groups;

R₅ is --COOR'" or --COR'" or --CONHR'" wherein R'" is C₁ -C₄ alkyl, C₂-C₅ alkenyl, C₃ -C₆ cycloalkyl, C₂ -C₄ alkynyl or a phenyl group,optionally substituted with one, two or three substituents which may bethe same or different and which are selected from a halogen atom and C₁-C₄ alkyl, C₁ -C₄ alkoxy and --CF₃ groups; or

a group of the formula Y or Y--O-- wherein Y is as defined above; or

(ii) R₂ represents a group of the formula --NH--B wherein B represents

a) hydrogen atom,

b) hydroxy group,

c) amino group,

d) a group of the formula Y--(NH)_(n) -- wherein Y is as defined aboveand n is 0 or 1, or

e) a group of the formula Y--O-- wherein Y is as defined above;

f) a group of the formula COR' wherein R' is as defined above, and R₃represents hydrogen, taken together with R, a bond.

R₁ is preferably a hydrogen atom, a hydroxy group or an acetoxy group;R₃ is preferably a hydrogen atom. R₂ preferably represents the group offormula NHB. B is preferably the chain of formula II.

R₄ is preferably phenyl or 2-furyl. R₅ is benzoyl or t-butoxycarbonylgroup.

The pharmaceutically acceptable salts are typically those salts formedwith pharmaceutically acceptable acids, both inorganic acids likehydrochloric, hydrobromic, sulfuric, phosphoric, diphosphoric, or nitricacid and organic acids such as citric, fumaric, maleic, malic, ascorbic,succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulfonic,benzenesulfonic or p-toluenesulfonic acid.

Further preferred compounds of the invention are: 13-aza-paclitaxel,13-aza-10-desacetoxy paclitaxel, 13-aza-10-desacetyl paclitaxel,13-aza-taxotere, 13-aza-10-deoxy-taxotere, 10deacetoxy-13-deoxy-13-imino paclitaxel, 10,13 dideoxy-13-imino taxotere,13-deoxy-13-imino paclitaxel, 13-deoxy-13-imino taxotere,10-deacetoxy-13-deoxy-13,14 ene-13-aza-paclitaxel, 13odeoxy-13,14ene-13-aza-paclitaxel, 10,13-dideoxy-13,14 ene-13 aza-taxotere, 13,14ene-13-aza-taxotere.

The suffix "aza" means that the oxygen atom of the substituent atposition 13 of the taxol structure has been replaced with an NH residue.

The present invention also provides a process for the preparation oftaxane derivatives of formula I as above defined. The following schemeillustrates the reaction sequence: ##STR4##

The process comprises, in a first step (a), the reaction of a7-protected-13-keto-baccatin derivative of the formula III wherein R₁,R_(a) and R_(c) are as defined above and R'_(b) or has the same meaningsof R_(b) except for OH or NH₂, either represents a protected amino orhydroxy group, in which the protecting group is trialkylsilyl or otherhydroxy protecting groups such as phenyldimethylsilyl,triisopropylsilyl, t-butyldimethylsilyl, dimethyl-(1-methyl,2-methyl)propylsilyl, t-butyldiphenylsilyl, acetyl, benzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl and the like, with hydroxylamine,O-methylhydroxylamine, methyl-hydrazine, N,N-dimethylhydrazine, or withammonia or an ammonium salt such as ammonium chloride, bromide orformate and optionally acylating the resulting compound thereby to givea compound of formula IV, IVb, IVd, V or VI, obtained as pure E or pureZ or as a mixture of E and Z isomers. Typically the reaction involvingthe 7-protected-13-keto-baccatin derivative is carried out in a solventsuch as pyridine at temperatures ranging from room temperature to theboiling point of the solvent. The optional acylation of the intermediateof formula IVb may be carried out with a conventional acylating agent,such as acetic anhydride or benzoyl chloride to give a compound IVd.

It is to be noted that the compound of the formula IVd may exist also asa tautomer of formula IV'd ##STR5## that is R₃ and R taken together area bond, which can be partially reduced and deprotected to give thederivative of the formula IX as defined above.

In a second step (b), the 13-hydrazones of formula VI may be reactedwith anhydrous hydrazine to give a taxane derivative of formula VII,which is then optionally reduced a hydrazine derivative of formula VIIIusing standard procedures (e.g. reduction with catalytical hydrogenationsuch as in the presence of Raney Ni, Pt or Pd).

In step (c), the resultant 13-oxime of formula IV may be partiallyreduced, e.g. with boranes, borohydrides or with catalyticalhydrogenation such as in the presence of Raney Nickel, Pt or Pd, to givethe hydroxylamino derivatives of the formula IVa or the iminoderivatives of the formula IVb.

In this step, when the reduction is carried out in the presence ofNi/Raney and hydrazine, there are obtained also derivatives of theformula IVb wherein R₁ represents hydrogen atom. The compound of formulaIVb may be oxidized in the presence of organic peracid, such as m-chloroperbenzoic acid to give again a compound of the formula IV and thederivative of formula IVc having R=OH.

In step (d), the compound of formula IV, IVa,; IVc, V or VI canoptionally be reduced to give the amino derivative of formula IX usingstandard procedures (e.g. reduction with borohydrides or by catalytichydrogenation).

In step (e), the C-13 derivatives of formula IV, IVa, IVb, VII, VIII orIX can be acylated with an appropriately protected amino acid (thehydroxy group, if present, will be conveniently protected, for exampleas O-(1-ethoxyethyl)ether or as -triethylsilyloxy) or with a molecule ofthe formula Xa or Xb, Xc or Xd, optionally conveniently activated at thecarboxy group ##STR6## wherein R_(A) is a hydroxy protecting group,preferably wherein R_(A) is a hydroxy protecting group, preferably1-ethoxyethyl, triethylsilyl, t-butyldimethylsilyl, R_(B) is H or CH₃,R_(c) is CH₃ or an optionally substituted phenyl group, preferably 2,4dimethoxy or 4 methoxy phenyl group, R_(D) is an optionally substitutedphenyl group as for R_(c) and R₄ and R₅ are as defined above, in thepresence of a condensing agent such as -dicyclohexylcarbodiimide (DCC)or di-2-pyridylcarbonate (DPC), in toluene and 4-dimethylaminopyridine(DMAP) or --sodium hexamethyldisilazide (NaHMDS) in tetrahydrofurane(THF) to give the protected intermediate of the formula XI.

The useful intermediate derivatives of the formulas IV, IVa, IVb, IVc,IVd, IV'd, V, VI, VII VIII, IX and XI are also novel and are within thescope of the invention.

In the final optional step (f), the compounds of the formula IV, IVa,IVb, IVc, IVd, V, VI, VII, VII, IX and XI are then deprotected and ifwanted reduced, when R_(b) ' is azido group, to give the said taxanederivative of the formula I. In this final step, when R_(b) ' is aprotected amino or hydroxy group, the deprotection is carried out forexample by treatment with (n-Bu)₄ NF, HF/Pyridine, HF/MeCN, Zn/AcOH.When the acylating groups employed in step (e) were protected, theprotecting groups are conveniently removed by appropriate methods,in thelast step (f), for example when the acylating molecula of formula X_(c),as above defined, is used, the protecting group is removed in acidicconditions, such as with HCl/MeOH or EtOH, HCOOH 99%, CF₃ CO₂ H organicsolvent (CH₂ Cl₂). The resultant compounds of the formula I may also beconverted into different compounds of the formula I by appropriate knownreactions, after necessary protections, for example the compounds offormula I wherein R_(a) =R_(c) =H, and R_(b) is OH, may be convertedinto a compound of formula I wherein R_(a) and R_(b) taken together forma bond by protection of the hydroxy group, reaction with triflicanhydride and treatment with a base. The preparation of the startingcompounds of the formula III, Xa, Xb, Xc and Xd are known or may becarried out according to known methods; for example7-triethylsilyl-3-keto-baccatin (III, R=triethylsilyl, R₁ =OCOCH₃) hasalready been described see J. Chem. Soc., Chem. Commun., (1994), 295,Chem. Comm. (1970), 216, J.A.C.S., (1971), 93, 2325, TetrahedronAsymmetry 1992, 3, 1007, JOC 1991, 56, 1681, Tetrahedron 1992, 48, 6985,Tetrahedron Letters 1992, 33, 5185, JOC 1993, 58, 1287, EP-A 400971,1990.!

In a further aspect, the present invention also provides a compound offormula Ia ##STR7## wherein R_(a), R_(b), R_(c) and R₁ are as abovedefined, R₇ is hydrogen atom or an acyl residue of formula COR' or Y,wherein Y and R' are defined above and the pharmaceutically acceptablesalt thereof.

The compound of formula Ia and the pharmaceutically acceptable saltthereof may be prepared by a process which comprises:

(a) reducing a compound of the formula IVb as above defined, optionallyin the presence of an acylating agent, to give a compound of formula XII##STR8## wherein R₁, R_(a), R_(b) ', R_(c) and R₇, are as above definedexcept that R₇ is not a hydrogen atom,

b) deprotecting the resultant compound of the formula XII to give acompound of formula Ia and

c) optionally salifying the thus obtained compound of formula Ia to givea pharmaceutically acceptable salt thereof. Step (a) may be effected byusing standard conditions such as reduction with a borohydride such assodium cyanoborohydride or catalytic hydrogenation.

Step (b) can be carried out as described above for step (f) Theappropriate acylating agent may be selected from the group ofactivated/protected carboxylic acid derivatives, such as aceticanhydride, benzoyl chloride, cinnamoyl chloride, isobutanoylchloride andthe like.

BIOLOGICAL ACTIVITY

The cytotoxic activity of the compounds may be evaluated on B₁₆ -F₁₀murine melanoma cell line which was responsive to paclitaxel. The modeof action of the compound may also be tested on the tubulinassembly-disassembly assay in comparison with taxol a referencecompound.

(A) In vitro drug sensitivity assay.

Exponentially growing B₁₆ -F₁₀ murine melanoma cells were seeded (2×10⁴/ml) in RPMI 1640 medium supplemented with 10% heat-inactivated fetalcalf serum and 2 mM glutamine in 24-well plates (Costar). Scaledconcentrations of tested compounds were added immediately after seeding.The inhibition of cell growth was evaluated by counting cells with aCoulter counter after 24 hrs incubation. For each tested compoundconcentration triplicate cultures were used. The antiproliferativeactivity of the tested compounds was calculated from dose-responsecurves and expressed as IC₅₀ (dose causing 50% inhibition cell growth intreated cultures relative to untreated controls).

(B) Microtubule assembly-disassembly assay.

Calf brain tubulin was prepared by two cycles of assembly-disassembly(Shelanski M. L., Gaskin F. and Cantor C. R., Proc. Natl. Acad. Sci.U.S.A. 70, 765-768, 1973) and stored in liquid nitrogen in MAB (0.1MMES, 2.5 mM EGTA, 0.5 mM MgSO₄ 0.1 mM EDTA, 0.1 mM DTT pH 6.4). All theexperiments were carried out on protein stored for less than 4 weeks.Before each experiment, the tubulin was kept 30 min at 4° C. Assemblywas monitored by the method of Gaskin et al. (Gaskin F., Cantor C. R.and Shelanski M. L., J. Molec. Biol. 89, 737-758, 1974).

The cuvette (1 cm path) containing tubulin (1 mg/ml) and 1 mM GTP wasshifted to 37° C. and continuous turbidity measurements were made at 340nm on a Perkin-Elmer 557 double wavelength, double beamspectrophotometer equipped with an automatic recorder and athermostatically regulated sample chamber. After 30 minutes, 4 mM CaCl₂was added and depolymerisation was measured for 10 minutes as decreasedturbidity. At regular intervals of 15 minutes scaled doses of the testedcompounds were added and variations in the turbidity were monitored.Data are expressed as percentage of repolymerization induced by thetested compounds.

The taxane derivatives of formula I and Ia are thus antitumour agents.They may also be useful for the preparation of other antitumour agents.A human or animal suffering from a tumour may thus be treated by amethod which comprises the administration thereto of an effective amountof a taxane derivative of formula I or Ia or a pharmaceuticallyacceptable salt thereof according to the invention. The condition of thehuman or animal may thereby be improved. Examples of tumours that can betreated are sarcomas, carcinomas, lymphomas, neuroblastomas, melanomas,myelomas, Wilms tumour, leukemias and adenocarcinomas. Taxanederivatives of formula I or Ia pharmaceutically acceptable salts thereofcan be used to treat ovarian cancer, platinum-resistant ovarian cancer,metastatic breast cancer, non-small cell lung cancer, and head and neckcancer. The invention also provides a pharmaceutical composition whichcomprises, as active ingredient, a compound of formula I or Ia or apharmaceutically acceptable salt thereof according to the invention anda pharmaceutically acceptable carrier or diluent. The composition of theinvention is usually prepared following conventional methods and isadministered in a pharmaceutically suitable form. Administration can bemade by any of the accepted ways for administration of antitumour agentssuch as intravenous, intramuscular or subcutaneous injection or topicalapplication. For systemic injection the active compound may be, e.g.,dissolved in a vehicle consisting of a mixture of polyoxyethylatedcastor oil (Chremophor EL) 50% and ethanol 50% and then diluted withglucose 5% solution at the desired concentration, or in otherpharmaceutically suitable carriers. The amount of the active compoundadministered depends on the treated subject, age, weight, sex etc., andthe severity of the affliction. The method of administration depends onthe judgement of the prescribing physician. A suitable dosage for anaverage 70 kg person may range from about 0.01 g to about 1 g per day.

The following Examples illustrate the invention but they are notintended to limit it thereto.

EXAMPLE 1 (E)-7-O-triethylsilyl-13-deoxy-13-oxymino-baccatin

7-O-triethylsilyloxy-13-keto-baccatin (260 mg, 0.37 mmol) andhydroxylamine hydrochloride (130 mg, 1.87 mmol) were dissolved inpyridine (3 mL) and heated to reflux for 12 hours. After evaporatingpyridine under vacuum, the residue was dissolved in ethyl acetate,washed with 0.5N HCl (×2), with water, dried over Na₂ SO₄ andconcentrated to give a crude product, containing the (E)-oxime, the(Z)-oxime and some starting ketone. The oximes were separated on silicagel (eluant n-hexane/ethyl acetate 3:1).

The (E)-oxime was isolated as a white solid (100 mg, 38% yield).

TLC (n-hexane/ethyl acetate 1:1); Rf=0.54. ¹ H NMR (CDCl₃, 400 MHz):0.5-0.7 (m,6H,Si(CH₂ CH₃)₃), 0.92 (t,J=8.0 Hz, 9H,Si(CH₂ CH₃)₃), 1.08(s,3H,17), 1.23 (s,3H,16), 1.66 (s,3H,19), 1.75 (s,1H,OH-1), 1.87 (m,1H,6β), 2.21 (s,3H,COCH₃ -10), 2.22 (s,3H,COCH₃ -4), 2.26 (s,3H,18),2.54 (m, 1H,6α), 2.78 (d,J=19.6 Hz,1H,14-β), 3.02 (d,J=19.6 Hz,1H,14-α),3.80 (d,J=6.7 Hz,1H,3), 4.13(d,J=8.4 Hz,1H,20β), 4.32(d,J=8.4Hz,1H,20α), 4.49 (dd,J=6.8,10.5 Hz,1H,H-7), 4.94 (dd,J=9.4,1.8Hz,1H,H-5), 5.67(d,J=6.7 Hz, 1H,2), 6.61 (s,1H,10), 7.4-8.2 (m,5H,phenyl), 8.8 (bs, 1H, NOH).

EXAMPLE 2 (Z)-7-O-triethylsilyl-13-deoxy-13-oxymino-baccatin

The (Z)-oxime was isolated as a white solid (30 mg, 11% yield), (seeexample 1)

TLC (n-hexane/ethyl acetate 1:1); Rf=0.30. ¹ H-NMR(400 MHz, CDCl₃): 0.60(m, 6H, Si(CH₂ CH₃)₃), 0.92 (m, 9H,Si(CH₂ CH₃ )₃), 1.13 (s,3H,17), 1.21(s,3H,16), 1.66 (s,3H,19), 1.79 (s,1H,OH-1), 1.90 (m, 1H,6β), 2.18(s,3H, COCH₃ -10), 2.23 (s,3H, COCH₃ -4), 2.43 (s,3H,18), 2.54 (d,J=17.6 Hz,1H,14β), 2.56 (m, 1H, 6α), 3.10 (d, J=17.6 Hz,1H,14α), 3.76(d, J=6.4 Hz,1H,3), 4.17 (d, J=8.5 Hz,1H,20β), 4.34 (d, J=8.5 Hz, 1H,20α), 4.54 (dd, J=6.7 Hz,1H,7), 4.98 (dd, J=1.5, 9.4 Hz,1H,5), 5.65 (d,J=6.4 Hz,1H,2), 6.61 (s, 1H,10), 7.4-8.1 (m, 5H,phenyl).

EXAMPLE 3 (E)-13-deoxy-13-oxymino-baccatin

To 7-O-triethylsilyloxy-13-deoxy-13-(E)oxymino-baccatin (80.4 mg, 0.11mmol), dissolved in dry tetrahydrofurane (5 mL), and stirred at 0° C.under nitrogen, tetrabutylamonium fluoride (70 mL) was added, thereaction mixture was let to warm up to room temperature and stirred for14 hours. The mixture was diluted with ethyl acetate, washed with water,then with brine and dried over Na₂ SO₄. After concentration 62 mg (0.1mmol, 90% yield) of desired compound was obtained.

TLC (n-hexane/ethyl acetate 1:1.5); Rf=0.32. ¹ H NMR (CDCl₃, 400 MHz):1.14 (s,6H,16+17), 1.66 (s,3H,19), 1.75 (s,1H,OH-1), 1.87 (m, 1H,6β),2.14, 2.20, 2.27 (three singlets,9H, COCH₃ -10+COCH₃ -4+18), 2.56(m,2H,6α+OH-7), 2.80 (d,J=19.6 Hz,1H,14-β), 3.04 (d,J=19.6 Hz,1H,14-α),3.81 (d,J=6.7 Hz,1H,H-3), 4.14 (d,J=8.2 Hz,1H,20β), 4.32 (d,J=8.2Hz,1H,20α), 4.46 (m, 1H,7), 4.97 (dd,J=2.0, 9.7 Hz, 1H,5), 5.66(d,J=6.7Hz,1H,2), 6.45 (s,1H,10), 7.4-8.2 (m, 5H,phenyl), 8.0 (bs, 1H,NOH).

FAB-MS=m/Z 598 M-H!

EXAMPLE 4 (Z) -13-deoxy-13-oxymino-baccatin

To 7-O-triethylsilyloxy-13-deoxy-13-(Z)-oxymino-baccatin (77.3 mg, 0.108mmol), dissolved in pyridine (2.5 mL) and stirred at 0° C. undernitrogen, 70% HF pyridine complex (0.25 ml) was added, the reactionmixture was let to warm up to room temperature and stirred for 6 hours.Additional HF pyridine complex (0.125 mL) was added and the mixturestirred at room temperature 2 hours longer. After concentration undervacuum, 66 mg of crude material was obtained. Purification bychromatography (silica gel, eluant=pet.ether/ethyl acetate 7:8) yieldedthe desired product, as a white solid (40.7 mg, 63% yield).

TLC (n-hexane/ethyl acetate 1:1.5), Rf=0.22. ¹ H-NMR(400 MHz, CDCl₃):1.13 (s,3H,16), 1.21 (s,3H,17), 1.66 (s,3H,19), 1.89 (m, 1H,6β), 2.24,2.26, 2.32 (three singlets, 9H, COCH₃ -4+COCH₃ -10+18), 2.59 (m,3H,OH-7+14β+6α), 3.10 (d, J=17.6 Hz,1H,14α), 3.72 (d, J=6.7 Hz,1H,3),4.17 (d, J=8.2 Hz,1H,20α), 4.34 (d, J=8.2 Hz,1H,20α), 4.50 (m, 1H,7),5.02 (dd, J=2.1, 9.6 Hz,1H,5), 5.65 (d, J=6.7 Hz,1H, 2), 6.44 (s,1H,10), 7.4-8.1 (m, 5H, phenyl).

FAB-MS: m/Z 598 M-H!

EXAMPLE 5 (E)-13-deoxy-13-O-(S)-N-(tertbutoxycarbonyl)-α-phenylglycyl!-oxymino baccatin and(E)-13-deoxy-13-O-(R)-N-(tertbutoxycarbonyl)-α-phenylglycyl!-oxymino-baccatin

A solution of (E)-13-deoxy-13-oxymino-baccatin (117 mg, 0.195 mmol),1,3-dicyclohexylcarbodiimide (DCC, 100 mg, 0.48 mmol),(S)-BOC-L-α-phenyl-glycine (100 mg, 0.4 mmol), N,N-dimethyl pyridine(DMAP, cat. amount) in toluene (12 mL) was stirred at room temperaturefor 7 hours, the reaction mixture was filtered and concentrated to givea crude product (255 mg) that was purified by chromatography (silicagel, eluant: n-hexane/ethyl acetate 1.5:1) and then by preparative TLC(eluant: n-hexane/ethyl acetate 1:1). Two products were obtained,identical except for the stereochemistry of the carbon in the sidechain: isomer 1 (24 mg, 15%), isomer 2 (31 mg, 19%). Isomer 1: TLC(n-hexane/ethyl acetate 1:1); Rf=0.34. ¹ H-NMR (400 MHz, CDCl₃): 1.05(s,3H,17), 1.11 (s,3H,16), 1.45 (s, 9H, t-Bu), 1.62 (s,3H,19), 1.78(bs,1H, OH-1), 1.84 (m, 1H,6β), 1.95 (s, 3H, CH₃ CO-4), 2.21 (s,3H,18),2.27 (s, 3H,CH₃ CO-10), 2.54 (m, 2H, 6α+OH-7), 2.66 (d,J=19.9Hz,1H,14β), 3.02 (d, J=19.9 Hz, 1H, 14α), 3.76 (d, J=6.7 Hz, 1H, 3),4.08 (d, J=8.5 Hz, 20β), 4.31 (d,J=8.5 Hz,20α), 4.44 (dd, J=6.7,10.5Hz,1H, 7), 4.91 (d,J=8.5 Hz,1H,5), 5.50 (d, J=7.4 Hz,1H, NH-3'), 5.56(d, J=7.4 Hz,1H, 2'), 5.61 (d, J=6.7 Hz,1H,2), 6.42 (s,1H, 10), 7.2-8.2(m, 10H, two phenyls).

(FAB-MS=m/z 834 (M+H) Isomer 2=TLC (n-hexane/ethyl acetate 1:1);Rf=0.29. ¹ H-NMR (400 MHz, CDCl₃): 1.11 (s, 3H, 17), 1.12 (s, 3H,16),1.25 (s, 3H, COCH₃ -4), 1.42 (s, 9H, t-Bu), 1.60 (s, 3H, 19), 1.80 (m,1H, 6β), 1.85 (s, 1H, OH-1), 2.19 (s, 3H, 18), 2.27 (s, 3H, COCH₃ -10),2.49 (m, 2H, 6α+OH-7), 2.87 (s, 2H,14), 3.70 (d, d, J=6.7 Hz, 1H, 3 ),4.04 (d, J=8.5 Hz, 1H, 20β), 4.23 (d, J=8.5 Hz, 1H, 20α), 4.39 (dd,J=6.7,10.8 Hz,1H,7), 4.83 (dd, J=1.9,9.5 Hz,1H,5), 5.48 (d, J=7.0Hz,1H,2'), 5.60 (d, J=6.7 Hz,1H,2), 5.65 (d, J=7.0 Hz,NH-3'), 6.40(s,1H, 10), 7.3-8.1 (m,10H, two phenyls).

FAB-MS: m/z 834 (M+H)

EXAMPLE 6 (Z) -13-deoxy-13-O-(S)-N-(tertbutoxycarbonyl)-α-phenylglycyl!-oxymino-baccatin

A solution of (Z)-13-deoxy-13-oxymino-baccatin (37 mg, 0.06 mmol), DCC(24 mg, 0.12 mmol), BOC-L-α-phenylglycine (20 mg, 0.08 mmol), DMAP (cat.amount) in toluene (4 mL) was stirred at room temperature for 2.5 hours.The reaction mixture was filtered and concentrated to give a crudeproduct (76 mg) that was purified by chromatography (silica gel, eluant:n-hexane/ethyl acetate 11:14) to yield the title product as a whitesolid (30 mg, 60% yield).

TLC (n-hexane/ethyl acetate 1:1); Rf=0.27. ¹ H-NMR(400 MHz, CDCl₃): 1.06(s,3H,17), 1.10 (s,3H,16), 1.45 (s, 9H, t-Bu), 1.65 (s,3H,19), 1.75(s,1H,OH-1), 1.88 (m, 1H, 6β), 2.18 (s,3H,18), 2.20 (s,3H,COCH₃ -4),2.28 (s,3H, COCH₃ -10), 2.43 (d, J=4.1 Hz,1H,OH-7), 2.57 (m, 1H,6α),2.79 (d,J=18.2 Hz,1H,14β), 3.18 (d,J=18.2 Hz,1H,14α), 3.64 (d,J=6.6Hz,1H,3), 4.16 (d,J=8.5 Hz,1H,20β), 4.32 (d,J=8.5 Hz,1H,20α), 4.45 (m,1H,7), 4.97 (dd,J=2.2, 9.5 Hz,1H,5), 5.50 (m,2H, 2'+NH-3'), 5.62(d,J=6.6 Hz,1H,2), 6.37 (s,1H,10), 7.2-8.1 (m, 10H,two phenyls).

FAB-MS: m/Z 834 (M+H)⁺

EXAMPLE 7 7-O-triethylsilyl-13-deoxy-13-imino-baccatin

To a solution of 7-O-triethylsilyloxy-13-oxymino-baccatin (mg100, 0.14mmol) and 51% hydrazine hydrate (350 mL) in ethanol (7 mL), Aldrich W-2Raney-nickel (100 mg, as aqueous slurry, after washing with water andethanol) was added. The reaction mixture was stirred at room temperaturefor 12 hours, then was filtered through celite and purified bypreparative TLC (eluant: n-hexane/ethyl acetate 1:4) to give the titlecompound (25 mg, 25% yield) as a white solid.

TLC (n-hexane/ethyl acetate 1:4); Rf=0.32. ¹ H-NMR (400 MHz, CDCl₃):0.59 (m, 6H, Si(CH₂ CH₃)₃), 0.92 (t, J=7.8 Hz, 9H, Si(CH₂ CH₃ )₃), 1.11(s,3H,17), 1.25 (s,3H,16), 1.66 (s,3H,19), 1.87 (m, 1H,6β), 2.19, 2.21,2.28 (three singlets, 9H, CH₃ CO-4+CH₃ CO-10+18), 2.52 (m, 1H,6α), 2.69(d,J=19 Hz, 1H, 14b), 3.10 (d, J=19 Hz, 1H, 14α), 3.88 (d, J=6.8 Hz, 1H,3), 4,14 (d, J=8.5 Hz,1H,20β), 4.31 (d,J=8.5 Hz,1H,20α), 4.48 (m, 1H,7),4.93 (d, J=9.7 Hz,1H,5), 5.66 (d, J=6.8 Hz,1H,2), 6.60 (s,1H,10),7.5-8.1 (m, 5H, phenyl)

EXAMPLE 8 7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin

To a solution of 7-O-triethylsilyloxy-13-oxymino-baccatin (50 mg, 0.07mmol) and 51% hydrazine hydrate (158 mL) in ethanol (3 mL), Raney-nickelaqueous slurry (50 mg) was added. The reaction mixture was stirred atroom temperature for 3 hours, then was filtered through celite andpurified by preparative TLC (eluant: n-hexane/ethyl acetate 1:4) to givethe title compound (40 mg, 90% yield) as a white solid.

TLC (n-hexane/ethyl acetate 1:4); Rf=0.22. ¹ H-NMR(400 MHz, CDCl₃): 0.58(m, 6H, Si(CH₂ CH₃)₃), 0.95 (t, J=7.9 Hz,9H, Si(CH₂ CH₃ )₃), 1.13(s,3H,17), 1.19 (s,3H,16), 1.59 (s,3H,19), 1.86 (m, 1H,6β), 2.07 (d,J=1.2 Hz,3H, 18), 2.20 (S, 3H,OCOCH₃), 2.50 (m, 1H, 6α), 2.68 (d,J=18.7Hz,1H,14β), 3.09 (d,J=18.7 Hz,1H, 14α), 3.60 (dq,J=14.5,1.2 Hz,1H,10β),3.93 (d,J=14.5 Hz,1H,10α), 4.07 (d,J=6.5 Hz,1H,3), 4.12 (d, J=8.2Hz,1H,20β), 4.31 (d,J=8.2 Hz,1H,20α), 4.50 (dd,J=6.7,10.5 Hz,1H,7), 4.93(d,J=7.6 Hz,1H,5), 5.64 (d, J=6.5 Hz,1H,2), 7.4-8.1 (m,5H, phenyl).

FAB-MS=m/z 640 M+H!⁺.

EXAMPLE 9 10-Deacetoxy-13-deoxy-13-imino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (34 mg, 0.053mmol) in THF (4 mL) at 0° C., a 1M solution of tetrabutylammoniumfluoride in THF (60 μL) was added and the reaction mixture was stirredfor 2 hours at 0° C. The reaction mixture was poured into ice-water andextracted with ethyl acetate. The organic layer was washed with brine,water, dried over Na₂ SO₄ and concentrated under vacuum. The crudeproduct was purified by silica gel chromatography (eluant:dichloromethane/methanol 19:1) yielding 24 mg of the title compound(86%);

TLC (dichloromethane/methanol 19:1); Rf=0.27. ¹ H-NMR (400 MHz, CDCl₃):1.14 (s,3H,17); 1.19 (s,3H, 16); 1.61 (s, 3H,19); 1.78 (m,1H,6β); 2.06(d, J=1.2 Hz,3H,18); 2.20 (s, 3H,CH₃ CO); 2.63 (m, 1H, 6α); 2.69 (dd,J=18.8,1.1 Hz, 1H, 14β); 3.12 (d, J=18.8 Hz,1H,14α); 3.67 (dq,J=14.9,1.2 Hz,1H,10β); 4.00 (d, J=14.9 Hz,1H,10α); 4.14 (m, 2H,20β+3);4.36 (m,2H, 20α+7); 4.95 (dd, J=9.4, 2.1 Hz,1H,5); 5.68 (dd, J=6.8, 1.1Hz,1H,2); 7.4-8.1 (m,5H, phenyl).

EXAMPLE 10 7-O-triethylsilyl-11-hydro-12,13ene-13-deoxy-13-amino-baccatin

A solution of 7-O-triethylsilyloxy-13-deoxy-13-imino-baccatin (60 mg,0.086 mmol), para-toluensulfonic acid (10 mg), NaBH₃ CN (60 mg) inmethanol (1 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated, dissolved in ethyl acetate, theorganic layer was washed with brine and water, dried over Na₂ SO₄ andconcentrated to give the desired product (60 mg, quant.).

TLC (n-hexane/ethyl acetate 2:3); Rf=0.45. ¹ H-NMR(400 MHz, CDCl₃): 0.54(m, 6H, Si(CH₂ CH₃)₃), 0.89 (t, J=7.9 Hz, 9H, Si(CH₂ CH₃)₃), 1.08(s,3H,16), 1.12 (s,3H,17), 1.60 (s,3H,19), 1.72 (s,3H,18), 1.85 (m, 1H,6β), 1.93 (m, 1H,14β), 2.17, 2.33 (two singlets, 6H, CH₃ CO-4+CH₃CO-10), 2.41 (s,1H,13), 2.49 (m, 1H, 6α), 2.66 (d,J=17.3 Hz,1H,14α),4.18 (d,J=5.5 Hz,1H,3), 4.24 (d,J=8.5 Hz,1H,20α), 4.40 (m,2H,20β+7),4.91 (dd,J=2.3, 9.7 Hz,1H,5), 5.50 (dd, J=1.8, 5.5 Hz,1H,2), 5.95(s,1H,10), 7.4-8.1(m, 5H, phenyl).

FD-MS=m/Z 699

EXAMPLE 11 7-O-triethylsilyl-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-amino-baccatin

A solution of7-O-triethylsilyloxy-10-deacetoxy-13-deoxy-13-imino-baccatin (26 mg,0.037 mmol), para-toluensulfonic acid (2 mg), NaBH₃ CN (mg35) inmethanol (2 mL) was stirred at room temperature for 20 minutes. Thereaction mixture was concentrated, dissolved in ethyl acetate, theorganic layer was washed with brine and water, dried over Na₂ So₄ andconcentrated to give the desired product (20 mg, 84% yield).

TLC (n-hexane/ethyl acetate 2:3); Rf=0.5. ¹ H-NMR (400 MHz, CDCl₃): 0.52(m,6H,Si(CH₂ CH₃)₃), 0.90(t, J=7.9 Hz, 9H,Si(CH₂ CH₃)3), 1.10(s,3H,17),1.15(s,3H,16), 1.59(s,3H,19), 1.86(m,1H,6β), 1.89(m,1H,14β),2.04(s,3H,18), 2.20(s,3H,OCOCH₃), 2.43(s,1H,13), 2.50(m,1H,6α),2.69(d,J=18.7 Hz,1H,14α), 3.55 (dq, J=14.5, 1.2 Hz,1H,10β),3.89(d,J=14.5 Hz,1H,10α), 4.08(d,J=6.5 Hz,1H,3), 4.12(d,J=8.2 Hz,1H,20α), 4.31 (d, J=8.2 Hz,1H,20α), 4.50(m, 1H,7), 4.93(d,J=7.6 Hz,1H,5),5.64(d,J=6.5 Hz,1H,2), 7.4-8.1(m, 5H, phenyl).

FD-MS:m/Z 641

EXAMPLE 12 7-O-triethylsilyl-13-deoxy-13-acetylimino-baccatin

To a solution of 7-O-triethylsilyl-13-deoxy-13-imino-baccatin (10 mg,0.014 mmol) in THF (1 mL) at 0° C., acetic anhydride (6 μL) was added.After 30 minutes stirring at 0° C. the reaction mixture was poured intocold water and extracted with ethyl acetate. The organic phase waswashed with brine and water, dried over Na₂ SO₄ and concentrated to givethe title compound (85% yield).

TLC (n-hexane/ethyl acetate 1:1); Rf=0.58.

EXAMPLE 13 7-O-triethylsilyl-10-deacetoxy-13-deoxy-acetylimino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (200 mg, 0.3mmol) in THF (12 mL) at 0° C., acetic anhydride (125 μL) was added.After 30 minutes stirring at 0° C. the reaction mixture was poured intocold water and extracted with ethyl acetate. The organic phase waswashed with brine and water, dried over Na₂ SO₄ and concentrated to givethe title compound (80% yield).

TLC (n-hexane/ethyl acetate 1:1); Rf=0.6. ¹ H-NMR (400 MHZ, CDCl₃):0.5-0.7(m, 6H, Si(CH₂ CH₃)₃); 0.95 (m, 9H, Si(CH₂ CH₃ )₃); 1.16(s,3H,17); 1.19 (s,3H,16); 1.60 (s,3H,19); 1.86 (m, 1H,6β); 2.04(s,3H,18); 2.18(s,3H,COCH₃ -4); 2.27 (d,J=19.0 Hz,1H,14β); 2.40(s,3H,NCOCH₃); 2.60 (m,1H,6α); 3.22 (d, J=19.0 Hz,1H,14α); 3.58 (d,J=14.4 Hz,1H,10β); 3.96 (d,J=14.4 Hz,1H,10α); 4.09 (m,2H,3+20β); 4.30(d,J=8.5 Hz, 1H,20α); 4.53 (dd,J=10.5; 7.0 Hz,1H,7); 4.90 (m,1H,5); 5.64(d,J=6.2 Hz,1H,2); 7.4-8.1 (m,5H,phenyl);

The title compound may be in equilibrium with the following tautomericform:

7-O-triethylsilyl-10-deacetoxy-13-deoxy-13,14-ene-13-acetylamino-baccatin

¹ H-NMR (400 MHZ, CDCl₃): 0.5-0.7 (m, 6H,Si(CH₂ CH₃)₃); 0.95(m,9H,Si(CH₂ CH₃ )₃); 1.11 (s,3H,16); 1.25 (s,3H,17); 1.66 (s,3H,19);1.90 (m,1H,6β); 1.93 (s,3H,18); 2.11 (s,3H,COCH₃ -4); 2.17(s,3H,NCOCH₃); 2.47 (m, 1H,6α); 3.54 (d,J=14.7 Hz,1H,10β); 3.74 (d,J=14.7 Hz,1H,10α); 3.86 (d,J=7.0 Hz,1H,3); 4.21,4.27 (two doublets,J=8.2Hz,2H,20); 4.39 (dd,J=10.2,6.7 Hz,1H,7); 4.90 (dd,J=9.4, 2.0 Hz,1H,5);5.79 (d, J=7.0 Hz,1H,2); 6.34 (s,1H,14); 6.74 (s,1H,NHCOCH₃); 7.4-8.1(m,5H,phenyl);

EXAMPLE 14 7-O-triethylsilyl-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-acetylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (36 mg, 0.056mmol) in THF (2.4 mL) at room temperature, acetic anhydride (120 μL) andNaBH₃ CN (72 mg) were added. After 40 minutes at room temperature, thereaction mixture was poured into cold water and extracted with ethylacetate. The organic phase was washed with brine and water, dried overNa₂ SO₄ and concentrated to give a crude product that waschromatographed on preparative TLC (eluant: n-hexane/ethyl acetate 3:7).The title compound was obtained in 56% yield.

TLC (n-hexane/ethyl acetate 1:1); Rf=0.17. ¹ H-NMR (600 MHz, CDCl₃):0.5-0.7 (m,6H,Si(CH₂ CH₃)₃); 0.8-1.0 (m,9H,Si(CH₂ CH₃ )₃); 1.12(s,3H,16); 1.21 (s,3H,17); 1.52 (s,1H,OH-1); 1.58 (s,3H,19); 1.73(s,3H,18); 1.89 (m,1H,6β); 2.10 (s,3H,CH₃ CONH); 2.34 (s,3H,CH₃ CO-4);2.42 (m,1H,6α); 2.57 (m,2H,11+14α); 2.83 (d, J=13.4 Hz,1H,10α); 2.96(m,2H,10β+14β); 3.78 (d,J=5.2 Hz,1H, 3); 4.22 (dd, J=7.1,10.7 Hz,1H,7);4.30, 4.36 (two doublets, J=8.5 Hz,2H,20); 4.89 (m,1H,5); 4.47 (dd,J=5.2, 1.1 Hz,1H,2); 6.52 (s,1H,CONH); 7.4-8.1 (m,5H,phenyl).

FAB-MS=m/z 683

EXAMPLE 15 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-acetylamino-baccatin

To a solution of 7-O-triethylsilyl-10-deacetoxy-13-deoxy-12,13ene-13-acetylamino-baccatin (44 mg, 0.064 mmol) in THF (4 mL) at 0° C.,1M tetrabutylammonium fluoride solution in THF (2×70 μL) was added intwo portions. After 2 hours at 0° C., the reaction mixture was pouredinto cold water and extracted with ethyl acetate. The organic phase waswashed with brine and water, dried over Na₂ SO₄ and concentrated to givea crude product that was chromotographed on preparative TLC (eluant:n-hexane/ethyl acetate 1:4). The title compound was obtained in 75%yield. TLC (n-hexane/ethyl acetate=1:4); Rf=0.1. ¹ H-NMR (400 MHz,CDCl₃): 1.11 (s,3H,16); 1.20 (s,3H,17); 1.61 (s,3H,19); 1.72 (s,3H,18);1.83 (m,1H,6β); 2.10 (s, 3H,CH₃ CONH); 2.34 (s,3H,CH₃ CO-4); 2.55(m,3H,6α+11+14α); 2.87 (dd,J=13.8 Hz,J=2.0 Hz,1H,10α); 2.97 (d,J=18.2Hz,1H,14α); 3.06 (dd, J=13.8, 11.4 Hz,1H,10β); 3.76 (d, J=5.3 Hz,1H,3);4.12 (m,1H,7); 4.32, 4.37 (two doublets, J=8.5 Hz,2H,20); 4.90(dd,J=9.4, 2.6 Hz,1H,5); 5.56 (d,J=5.3 Hz,1H,2); 6.53 (s,1H, CH₃ CONH);7.4-8.1 (m,5H,phenyl).

EXAMPLE 167-O-triethylsilyl-10-deacetoxy-13-deoxy-13-oxymino-14(β)-hydroxy-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (55 mg, 0.086mmol) in dichloromethane (3 mL), 50% metachloro perbenzoic acid (52 mg)was added and the reaction mixture stirred at room temperature for 1hour. More dichloromethane (20 mL) was added and the solution wasextracted with sat.solution of sodium hydrogencarbonate (4×25 mL) andthen washed with brine. The crude product was chromatographed onpreparative TLC (eluant=n-hexane/ethyl acetate 1:1). The title compoundwas obtained in 25% yield. Also the 13-oximino derivatives, described inExample 1, were isolated.

TLC (n-hexane/ethyl acetate 1:1); Rf=0.55. ¹ H-NMR (400 MHz, CDCl₃):0.5-0.7 (m,6H, Si(CH₂ CH₃)₂); 0.95 (m,9H,Si(CH₂ CH₃)₃ ;1.11 (s,3H,17);1.21 (s,3H,16); 1.64 (s,3H,19); 1.88 (m,1H,6β); 2.05 (s,3H,18); 2.26 (s,3H,COCH₃); 2.47 (m, 1H,6α); 3.58 (d, J=15.0 Hz,1H,10β); 3.89 (d, J=6.7Hz,1H,3); 3.92 (d, J=15.0 Hz,1H, 10α); 3.97 (s,1H,OH-1); 4.27, 4.29 (twodoublets, J=8.5 Hz,2H,20); 4.46 (dd, J=6.7, 10.6 Hz,1H,7); 4.77 (d,J=2.1 Hz,1H,OH-14); 4.90 (dd,J=1.7, 9.6 Hz,1H,5); 4.98 (d, J=2.1 Hz,14);5.82 (d, J=6.7 Hz,1H,2); 7.4-8.1 (m,5H,phenyl); 9.3 (bs, 1H, N--OH).

EXAMPLE 17 10-Deacetoxy-13-deoxy-13-acetylimino-baccatin (first method)

To a solution of 10-deacetoxy-13-deoxy-13-imino-baccatin (20 mg, 0.029mmol) in pyridine (0.5 mL) at 0° C., acetic anhydride (30 μL) was addedunder stirring. After 1 hour at 0° C. the reaction mixture was pouredinto cold brine and was extracted with ethyl acetate. The organic layerwas washed twice with water, dried over Na₂ SO₄ and concentrated undervacuum to yield 19.6 mg of the title product (91% yield).

TLC (hexane/ethyl acetate 1:1); Rf=0.7

EXAMPLE 18 10-Deacetoxy-13-deoxy-13-acetylimino-baccatin (second method)and 10-deacetoxy-13-deoxy-13,14 ene-13-acetylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-acetylimino-baccatin (23 mg,0.031 mmol) in THF (4 mL) at 0° C., 1M tetrabutylammonium fluoride inTHF (70 μL) was added. The reaction mixture was stirred at 0° C. for 2hours; then it was poured into ice-water and extracted with ethylacetate. The organic layer was separated, washed with brine, with water,dried over Na₂ SO₄ and concentrated under vacuum. The residue waspurified by preparative chromatography over silica gel (eluant:n-hexane/ethyl acetate 1:1). A mixture of the title products(keto-enolic equilibrium products) was obtained (20 mg, 95% yield)

TLC (hexane/ethyl acetate ); Rf=0.12 (I) and Rf=0.7 (Ia).

EXAMPLE 19 7-O-triethylsilyl-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-benzoylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (21 mg, 0.0328mmol) in anhydrous THF (2 mL) at 0° C., under nitrogen, benzoyl chloride(38 μL, 0.327 mmol) and NaBH₃ CN (41 mg) were added. After 1 hour at 0°C., the reaction mixture was dissolved in ethyl acetate. The organicsolution was poured into ice, the organic phase was washed with brineand dried over Na₂ SO₄ The crude product was purified by preparativechromatography over silica gel (eluant n-hexane/ethyl acetate 2:1) togive the title product (16 mg, 65%).

TLC (hexane/ethyl acetate 1:1); Rf 0.41. ¹ H-NMR (400 MHz, CDCl₃) 1.16(s,3H,17); 1.28 (s,3H,16); 1.61 (s,3H,19); 1.84 (s,3H,18); 1.90(m,1H,6β); 2.11 (s,3H,CH₃ CO); 2.46 (m,1H,6α); 2.64 (d, J=11.7 Hz, 1H,11); 2.70 (d, J=18.5 Hz,1H,14α); 2.90 (dd, J=13.5,1.2 Hz,1H,10α); 3.00(dd, J=13.5,11.7 Hz,1H,10β); 3.12 (d, J=18.5 Hz,1H,14β); 3.90 (d, J=5.3Hz,1H,3); 4.26 (dd, J=7.3,10.5 Hz, 1H, 7); 4.31, 4.35 (two doublets,J=8.5 Hz,2H,20); 4.90 (m,1H,5); 5.50 (dd, J=5.3,1.4 Hz,1H,2); 7.37(s,1H,PhCONH); 7.4-8.1 (m,10H,two phenyls).

EXAMPLE 20 7-O-triethylsilyl-10-deacetoxy-11-hydro-12 13ene-13-deoxy-13-isobutanoylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (30 mg, 0.047mmol) in anhydrous THF (3 mL) at 0° C., under nitrogen,isobutanoylchloride (40 μL) and NaBH₃ CN (60 mg) were added. After 50minutes at 0° C., the reaction mixture was poured into ice, the organicmaterial was extracted with ethyl acetate and washed with brine anddried over Na₂ SO₄. The crude product was purified by preparativechromatography over silica gel (eluant=n-hexane/ethyl acetate 7:3),yielding 24 mg of the title compound (72%).

TLC (n-hexane/ethyl acetate=7:3); Rf=0.51.

EXAMPLE 21 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-isobutanoylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-11-hydro-13-deoxy-12,13-ene-isobutanoyl-baccatin(24 mg, 0.034 mmol) in THF (2 mL), at 0° C. under nitrogen, 50 μL of 1Msolution of tetrabutylammonium fluoride in THF was added. After twohours to the reaction mixture ethyl acetate was added, the organicsolution was poured into ice, separated, washed with brine, water anddried over Na₂ SO₄. The crude product was purified by preparative TLC(eluant: n-hexane/ethyl acetate 1:3), yielding 14 mg (69%) of the titleproduct.

TLC (n-hexane/ethyl acetate 1:4); Rf=0.29. ¹ H-NMR (200 MHz, CDCl₃):1.06 (s,3H,17); 1.17, 1.21 (two d, J=6.8 Hz,CH(CH₃ )₂ ); 1.24 (s,3H,16);1.59 (s,3H,19); 1.69 (s,3H,18); 1.72 (s,1H,OH-1); 1.7-2.0(m,2H,6β+OH-7); 2.32 (s,3H,COCH₃); 2.3-2.7 (m,4H,(CH₃)₂ CHCO+11+6α+14);2.8-3.0 (m,2H,10α+14β); 3.04 (dd, J=11.2, 13.8 Hz,1H, 10β); 3.73 (d,J=5.3 Hz,1H, 3); 4.09 (m,1H,7); 4.29, 4.35 (two d, J=8.6 Hz,2H,20); 4.88(dd, J=2.5, 9.2 Hz,1H,5); 5.53 (dd, J=5.3, 1.0 Hz,1H,2); 6.51(s,1H,CONH); 7.4-8.1 (m,5H,phenyl).

EXAMPLE 22 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-henzoylamino-baccatin

The removal of the 7-O-triethylsilyl group was performed as described inExample 15.

The title compound was obtained in 75% yield.

TLC (n-hexane/ethyl acetate 1:2); Rf=0.24. ¹ H-NMR (200 MHz, CDCl₃):1.11 (s,3H,17); 1.25 (s,3H,16); 1.62 (s,3H,19); 1.75 (s,1H,OH-1); 1.81(s,3H,18); 1.85 (m,1H,6β); 2.09 (s,3H,CH₃ CO-4); 2.4-2.8 (m,3H,6α+11+14α); 2.91 (dd, J=2.5, 13.8 Hz,1H,10α); 3.0-3.2 (m,2H,10β+14β);3.84 (d, J=5.2 Hz,1H,3); 4.15 (m,1H,7); 4.27,4.35 (two doublets, J=8.5Hz,2H,20); 4.89 (dd, J=2.4, 9.2 Hz,1H,5); 5.57 (dd, J=1.0, 5.2 Hz,1H,2);7.34 (s,1H,CONH); 7.3-8.1 (m,10H, two phenyls).

EXAMPLE 237-O-triethylsilyl-10-deacetoxy-13-deoxy-13-phenylacetylimino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (20 mg, 0.031mmol) and phenylacetic acid (22 mg, 0.16 mmol) in anhydrous THF (2 mL),1,3-dicyclohexylcarbodiimide (36 mg, 0.174 mmol) and a few crystals ofN,N-dimethylaminopyridine were added at room temperature, under nitrogenwith stirring. After 40 minutes the reaction mixture was filtered oncelite, the filtrate was concentrated and purified on preparative TLC(eluant: n-hexane/ethyl acetate 2:1), yielding 20 mg (84%) of the titlecompound.

¹ H-NMR (200 MHz, CDCl₃): 0.5-0.7 (m, 6H, Si(CH₂ CH₃)₃); 0.9(m,9H,Si(CH₂ CH₃ )₃); 1.15 (s,3H,17); 1.20 (s,3H,16); 1.6 (s,3H,19); 1.9(m,1H,6β); 2.0 (s,3H,18); 2.1 (d, 1H,14β);); 2.4 (s,3H,CH₃ CO-4); 2.5(m,1H, 60); 3.3 (d,1H,14α); 3.55 (d,1H,10β); 3.75 (d,2H,CH₂ -phenyl);3.9 (d, 1H,10α); 4.05 (m,2H,3+20β); 4.25 (d, 1H,20α); 4.45 (dd,1H,7);4.90 (m,1H,5); 5.6 (d,1H,2); 7.2-8.1 (m,10H, two phenyls).

EXAMPLE 24 7-O-triethylsilyl-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-phenylacetylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-phenylacetylimino-baccatin(20 mg, mmol) in anhydrous THF (2 mL), cooled at 0° C., NaBH₃ CN (47 mg)and a few crystals of p-toluensulfonic acid were added under nitrogen,with stirring. After 2 hours brine was added to the reaction mixture andthe organic material was extracted with ethyl acetate. The organic layerwas dried over Na₂ SO₄, filtered and concentrated under vacuum. Thecrude product was purified by preparative TLC (eluant: n-hexane/ethylacetate 1.5:1), yielding 15 mg (75%) of the title product.

EXAMPLE 25 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-phenylacetylamino-baccatin

The removal of the 7-O-triethylsilyl group was performed as described inExample 15.

The title compound was obtained in 68% yield.

TLC (n-hexane/ethyl acetate 1:2); Rf=0.22. ¹ H-NMR (200 MHz, CDCl₃):1.07 (s,3H,16); 1.17 (s,3H,17); 1.49 (s,3H,18); 1.57 (s,3H,19); 1.64(s,1H,OH-1); 1.79 (m, 1H,6β); 2.06 (s,3H,CH₃ CO-4); 2.3-2.7 (m,3H,6α+11+14α); 2.7-2.9 (m,2H, 10α+14β); 3.01 (dd, J=11.3,13.7 Hz,1H,10β);3.5-3.8 (m, 3H,3+PhCH₂ CO); 4.04 (dd, J=6.9, 11.1 Hz,1H,7); 4.27,4.32(two doublets, J=8.5 Hz,2H,20); 4.82 (dd, J=2.5, 9.3 Hz,1H,5); 5.51 (dd,J=1.0, 5.3 Hz,1H,2); 6.49 (s, 1H, CONH); 7.2-8.1 (m,10H,two phenyls).

EXAMPLE 26 7-O-triethylsily-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-cinnamoylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (20 mg, 0.031mmol) in anhydrous THF (2 mL) at 0° C., under nitrogen with stirring,cinnamoylchloride (43 mg) and NaBH₃ CN (40 mg) were added. After 70minutes at 0° C., the reaction mixture was poured into ice-water andextracted with ethyl acetate. The organic solution was washed withbrine, dried over Na₂ SO₄ and concentrated under vacuum. The crudeproduct was purified by preparative chromatography over silica gel(eluant: dichloromethane/ethyl acetate 17:3), yielding 12 mg of thetitle compound (50%).

EXAMPLE 27 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-cinnamoylamino-baccatin

The removal of the 7-O-triethylsilyl group was performed as described inExample 15.

The title compound was obtained in 73% yield.

TLC (dichloromethane/methanol 19:1); Rf=0.46. ¹ H-NMR (200 MHz, CDCl₃):1.13 (s,3H,16); 1.24 (s,3H,17); 1.60 (s,3H,19); 1.78 (s,3H,18); 1.83(m,1H,6β); 2.29 (s,3H,CH₃ CO-4); 2.5-2.8 (m,3H, 6α+11+14α); 2.89(dd,J=2.1,13.7 Hz,1H,10α); 3.0-3.3 (m,2H,10β+14β); 3.81 (d,J=5.1Hz,1H,3); 4.12 (m, 1H,7); 4.30, 4.36 (two doublets, J=8.6 Hz,2H,20);4.90 (dd, J=2.3,9.3 Hz,1H,5); 5.56 (d, J=5.1 Hz,1H,2); 6.51 (d,J=15.5Hz,1H,Ph-CH═CH); 6.74 (s,1H,CONH); 7.69 (d,J=15.5 Hz,1H,Ph-CH═CH);7.3-8.1 (m,10H, two phenyls).

EXAMPLE 287-O-Triethylsilyl-10-deacetoxy-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylimino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-imino-baccatin (50 mg, 0.078mmol) and (4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-carboxylic acid (35 mg, 0.107 mmol), in toluene (7 mL),N,N-dicyclohexylcarbodiimide (30 mg, 0.145mmol) and4-dimethylaminopyridine (7.5 mg, 0.061 mmol) were added and the reactionmixture was stirred under nitrogen at room temperature for 30 minutes.The reaction mixture was filtered, the solvent evaporated under vacuumand the crude product was purified by preparative chromatography oversilica gel (eluant: n-hexane/ethyl acetate 2:1), yielding 57 mg of thetitle compound (76%).

TLC (n-hexane/ethyl acetate 1:1); Rf 0.58. ¹ H-NMR (600 MHz, CDCl₃):0.4-0.7 (m,6H,Si(CH₂ CH₃)₃); 0.81,1.11 (two s,6H,16+17); 0.94(m,9H,Si(CH₂ CH₃)₃); 1.58 (s,3H,19); 1.85 (m,1H,6β); 1.91,1.93,1.93(three s,9H,18+2 CH₃ -5'); 2.35 (d, J=19.0 Hz,1H,14β); 2.41 (s,3H, COCH₃-4); 2.47 (m,1H,6α); 3.23 (d, J=19.0 Hz,1H,14α); 3.52 (d, J=14.5Hz,1H,10β); 3.88 (d, J.=14.5 Hz,1H,10α); 4.02 (d, J=6.6 Hz,1H,3); 4.07(d,J=8.5 Hz,1H,20β); 4.29 (d,J=8.5 Hz,1H,20α); 4.48 (dd,J=6.8,10.5Hz,1H,7); 4.58, 5.22 (two d, J=8.1 Hz, 2H, 2'+3+); 4.87 (d,J=8.5Hz,1H,5); 5.60 (d, J=6.6 Hz,1H,2); 6.8-8.1 (m,15H,three phenyls).

EXAMPLE 29 10-Deacetoxy-13,14ene-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl -4-phenyloxazolidin-5-yl)-carbonylamino-baccatin

7-O-Triethylsilyl-10-deacetoxy-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylimino-baccatin (20 mg, 0.021 mmol) wasdissolved in a mixture of methanol (1 mL), 0.1N HCl (1 mL) and THF (0.5mL) and stirred for 20 hours at room temperature.

The solvent was evaporated under vacuum, water and ethyl acetate wereadded, the organic phase was separated and washed with water, dried overNa₂ SO₄ and concentrated. The crude product was purified by preparativechromatography over silica gel (eluant: n-hexane/ethyl acetate 3:7),yielding 10 mg of the title compound (50%).

TLC (n-hexane/ethyl acetate 1:5); Rf 0.56. ¹ H-NMR (200 MHz, CDCl₃):1.12, 1.33 (two s,6H,16+17); 1.65 (s,3H,19); 1.78 (m,2H,6β+OH-1); 1.90,1.97, 2.00, 2.01 (four s,12H,2 CH₃ -5'+18++CH₃ CO-4); 2.59 (m,1H, 6α);3.60 (d,J=15.5 Hz,1H,10β); 3.84 (d, J=15.5 Hz,1H,10α); 3.94 (d,J=7.0Hz,1H,3); 4.1-4.3 (m,3H,7+20); 4.55, 5.19 (two d, J=6.5 Hz,2H,2'+3');4.89 (m, 1H,5); 5.82 (d, J=7.0 Hz,1H,2); 6.35 (s,1H,14); 6.9-8.1(m,15H,three phenyls); 8.20 (s,1H, NH-13).

EXAMPLE 30 7-O-Triethylsilyl-10-deacetoxy-11-hydro-12,13ene-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylamino-baccatin

To a solution of7-O-triethylsilyl-10-deacetoxy-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylimino-baccatin (50 mg,0.052 mmol) in anhydrousTHF (6 mL), cooled to 0° C., under nitrogen, sodium cyanoborohydride (73mg, 1.16 mmol) and p-toluensulfonic acid (2 mg, 0.12 mmol) were added.The reaction mixture was stirred for 50 minutes, brine and ethyl acetatewere added and the organic phase was washed with brine, dried over Na₂SO₄, concentrated under vacuum and filtered through a short pad ofsilica gel to yield 48 mg of the title compound (96%).

TLC (n-hexane/ethyl acetate 1:1); Rf 0.5. ¹ H-NMR (600 MHz, CDCl₃):0.4-0.7 (m,6H,Si(CH₂ CH₃)₃); 0.93 (m,9H,Si(CH₂ CH₃)₃); 1.13, 1.23 (twos,6H,16+17); 1.47 (s,1H,OH-1); 1.58 (s,3H,19); 1.83 (s,1H,18); 1.90(m,1H, 6β); 2.01,2.02 (two s, 6H,2 CH₃ -5'); 2.29 (s,3H,COCH₃ -4); 2.45(m,1H,6α); 2.58 (d, J=18.5 Hz,1H,14α); 2.65 (d,J=12.2 Hz,1H,11); 2.87(d, J=18.5 Hz,1H,14β); 2.90 (d, J=13.7 Hz,1H,10α); 2.98 (dd, J=13.7,12.2Hz,1H,10β); 3.84 (d, J=5.1 Hz,1H,3); 4.2-4.4 (m,3H, 7+20); 4.55, 5.24(two d, J=6.8 Hz,2H, 2'+3'); 4.87 (m,1H,5); 5.46 (d, J=5.1 Hz,1H,2);7.76 (s,1H,NH-13); 6.9-8.1 (m,15H,three phenyls).

EXAMPLE 31 10-Deacetoxy-11-hydro-12,13ene-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylamino-baccatin

7-O-Triethylsilyl-10-deacetoxy-11-hydro-12,13 ene-13-deoxy-13-((4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyloxazolidin-5-yl)-carbonylamino-baccatin (14 mg, 0.014 mmol) wasdissolved in anhydrous ethanol (2 mL) containing 2N HCl (100 mL). Thereaction mixture was stirred for 2.5 hours at 40° C. The solvent wasevaporated under vacuum, brine and ethyl acetate were added, the organicphase was dried over Na₂ SO₄ and concentrated under vacuum. The residuewas purified by preparative TLC (eluant ethyl acetate/n-hexane 2:1) toyield 8 mg of the title compound (68%).

TLC (n-hexane/ethyl acetate 1:5); Rf 0.54. ¹ H-NMR (600 MHz, CDCl₃):1.13, 1.24 (two s,6H,16+17); 1.53 (s,1H,OH-1); 1.61(s,3H,19); 1.83(m,4H,18+6β); 1.99,2.02 (two s, 6H,2 CH₃ -5'); 2.29 (s,3H,COCH₃ -4);2.56 (m,1H,6α); 2.60 (d, J=18.6 Hz,1H,14α); 2.65 (d,J=11.6 Hz,1H,11);2.89 (d, J=18.6 Hz,1H,14β); 2.94 (dd, J=13.9,1.7 Hz,1H,10α); 3.10 (dd,J=13.9,11.6 Hz,1H,10β); 3.84 (d, J=5.1 Hz,1H,3); 4.16 (dd,J=7.8,10.7Hz,1H, 7); 4.30, 4.34 (two d,J=8.5 Hz,2H,20); 4.54, 5.22 (two d, J=6.6Hz,2H, 2'+3'); 4.89 (dd,J=9.2,2.3 Hz,1H,5); 5.54 (dd, J=5.1,1.1Hz,1H,2); 7.77 (s,1H,NH-13); 6.9-8.1 (m,15H,three phenyls).

We claim:
 1. A taxane derivative formula I: ##STR9## wherein Rrepresents a hydrogen atom or a hydroxy group, or taken together withR₃, a bond; R_(a) and R_(c) are hydrogens and R_(b) is hydroxy;R₁represents a hydrogen atom or OCOCH₃ ; and either(i) R₂ and R₃ togetherrepresent a group of the formula A--N═, as pure E or pure Z isomers oras a mixture of both E and Z isomers, wherein A represents:a hydrogenatom or a hydroxy, methoxy, acetoxy, amino, methylamino or dimethylaminogroup, or a group of the formula Y--NH-- wherein Y represents either(a)residue of an amino acid, optionally protected at the amino group as aN-benzoyl derivative or as a carbamate, or (b) a chain of the formulaII: ##STR10## wherein R₄ is a C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₆cycloalkyl group or a phenyl or heteroaryl group, optionally substitutedwith one, two or three substituents which may be the same or differentand which are selected from a halogen atom and C₁ -C₆ alkyl, C₁ -C₆alkoxy, or --CF₃ groups; and R₅ is --COOR'" or -COR'" or --CONHR'",wherein R'" is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl, C₂ -C₆alkynyl or a phenyl group, optionally substituted with one, two or threesubstituents which may be the same or different and which are selectedfrom a halogen atom and C₁ -C₆ alkyl, C₁ -C₆ alkoxy and --CF₃ groups;ora group of the formula Y or Y--O-- wherein Y is as defined above; agroup of the formula COR' wherein R' is as defined above; or (ii) R₂represents a group of the formula B--NH-- wherein B representsa)hydrogen atom b) hydroxy group, c) amino group, d) a group of theformula Y--(NH)_(n) -- wherein Y is as defined above and n is 0 or 1, ore) a group of the formula Y--O-- wherein Y is as defined above; f) agroup of the formula COR', wherein R' is as defined above; and R₃represents hydrogen;and pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein Y represents a chain of theformula II as defined in claim 1 or a residue of an amino acid selectedfrom glycine, phenylglycine, serine, 3-phenylserine and β-alanine.
 3. Acompound according to claim 1 wherein B represents hydrogen or a groupof the formula Y-- where Y is as defined in claim
 1. 4. A compoundaccording to claim 1 which is selected from the group consisting of13-aza paclitaxel, 13-aza-10-desacetoxy paclitaxel, 13-aza-taxotere,13-aza-10-deoxy taxotere, 13-aza-10 desacetyl paclitaxel13-aza-paclitaxel, 13-aza-10-desacetoxy paclitaxel, 13-aza-10-desacetylpaclitaxel, 13-aza-taxotere, 13-aza-10-deoxy-taxotere, 10deacetoxy-13-deoxy-13-imino paclitaxel, 10,13 dideoxy-13-imino taxotere,13-deoxy-13-imino paclitaxel, 13-deoxy-13-imino taxotere,10-deacetoxy-13-deoxy-13,14 ene-13-aza-paclitaxel, 13-deoxy-13,14ene-13-aza-paclitaxel, 10,13-dideoxy-13,14 ene-13 aza-taxotere, and13,14 ene-13-aza-taxotere.
 5. A process for preparing a taxanederivative of formula I as defined in claim 1, or a pharmaceuticallyacceptable salt thereof which process comprises: (a) reacting a7-protected-13-keto-baccatin derivative of formula III ##STR11## whereinR₁ R_(a) and R_(c) are as defined in claim 1 and R'_(b) is either R_(b)except for NH₂ or OH or a protected amino or hydroxy group, withhydroxylamine, O-methylhydroxylamine, methylhydrazine,N,N-dimethylhydrazine or with ammonia or an ammonium salt and optionallyacylating the resulting compound thereby to give a compound of formulaIV, IVb, IVd, IV'd, V or VI: ##STR12## wherein R' is as defined in claim1, R_(a), R'_(b), R_(c), and R₁ are as above defined, A₁ representsmethoxy or acetoxy and A₂ represents a methylamino or dimethylaminogroup;(b) optionally reacting the resultant 13-hydrazone of formula VIwith anhydrous hydrazine (H₂ N--NH₂) to give a taxane derivative offormula VII ##STR13## wherein R_(a), R'_(b), R_(c) and R₁ as abovedefined, which is then optionally reduced to a hydrazine derivative offormula VIII: ##STR14## wherein R_(a), R'_(b), R_(c) and R₁ are as abovedefined; (c) optionally partially reducing the said 13-oxime derivativeof formula IV to give the 13-hydroxylamine derivative of formula IVa orthe 13-imino derivative of formula IVb as defined above: (e) optionallyacylating the C-13 derivative of formula IV, IVa, Ivb VII, VIII or IXwith a protected amino acid or with a compound of formula Xa, Xb, Xc orXd optionally conveniently activated at the carboxy group: ##STR15##wherein R_(A) is a hydroxy protecting group and R_(B) is H or CH₃, R_(c)is CH₃ or an optionally substituted phenyl group, R_(D) is an optionallysubstituted phenyl group, R₄ and R₅ are as defined in claim 1, in thepresence of a condensing agent to give a protected intermediate of theformula XI: ##STR16## wherein R, R_(a), R'_(b), R_(c) are as abovedefined, and R₂ and R₃ are as defined in claim 1 or a protectedprecursor thereof, (f) ##STR17## (c') optionally oxidizing a derivativeof formula IVb as above defined to give a derivative of formula IVc,##STR18## wherein R₁, R_(a), R'_(b), and R_(C) are as defined above; (d)optionally reducing the 13-derivative of formula IV, IVa, IVc, V or VIto give the 13-amino derivative of formula IX: ##STR19## wherein R₁,R_(a), R'_(b) and R_(c) are as above defined and R is H orOH;deprotecting or reducing when necessary the resultant said compoundof the formula IV, IVa, IVb, IVc, IVd, V, VI, VII, VIII, IX or XI togive the said taxane derivative of the formula I; and (g) optionallysalifying the said taxane derivative of the formula (I) to give apharmaceutically acceptable salt thereof.
 6. A process according toclaim 5, wherein the protected intermediate of formula XI is: ##STR20##wherein R₆ is a hydroxy protecting group.
 7. A compound of the formulaIV, IVa, IVb, IVc, IVd, V, VI, VII, VIII, IX or XI as defined in claim5.
 8. A compound of formula Ia ##STR21## wherein R₁ R_(a), R_(b) andR_(c) are as defined in claim 1 and R₇ represents a hydrogen atom or anacyl residue of formula COR' or Y wherein Y and R' are defined in claim1 and pharmaceutically acceptable salts thereof.
 9. A process forpreparing a compound of formula Ia or a pharmaceutically acceptable saltthereof, which process comprises: ##STR22## (a) reducing a compound ofthe formula VIb ##STR23## wherein R', R₁, R_(a) and R_(c) are as definedin claim 1 and R'_(b) is either R_(b) as defined in claim 1 except forNH₂ or OH or a protected amino or hydroxy group, optionally in thepresence of an acylating agent, to give a compound of formula XII##STR24## wherein R_(a), R'_(b), R_(c), and R₁ are as defined above andR₇ is an acyl residue of formula COR' or Y where Y and R' are as definedin claim 1;(b) deprotecting the compound of formula XII to give saidcompound of the formula Ia; and (c) optionally salifying the thusobtained compound of formula Ia to give a pharmaceutically acceptablesalt thereof.
 10. A compound according to claim 8 which is selected fromthe group consisting of 10-deacetoxy-11 hydro-Δ¹²,13 -13-deoxy-13-azapaclitaxel, 10-deacetoxy-hydro-Δ¹²,13 -13-deoxy-13-aza taxotere,11-hydro-Δ¹²,13 -13-deoxy-13-aza paclitaxel, and 11-hydro-Δ¹²,13-13-deoxy-13-aza taxotere.
 11. A pharmaceutical composition whichcomprises a compound of the formula I as defined in claim 1 or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable diluent or carrier.
 12. A pharmaceuticalcomposition which comprises the compound of claim 8 or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable diluent or carrier.
 13. A method of treatinga tumor in a human or animal in need thereof, comprising administeringto said human or animal an effective amount of the taxane of claim 1.14. A method of treating a tumor in a human or animal in need thereof,comprising administering to said human or animal an effective amount ofthe compound of claim
 7. 15. A method of treating a tumor in a human oranimal in need thereof, comprising administering to said human or animalan effective amount of the compound of claim 8.